PROJECT SUMMARY Tobacco use in adolescents and young adults remains one of the most challenging public health issues in the United States. Adolescence and young adulthood represent a window of heightened vulnerability to tobacco use. A high proportion of adolescent tobacco users develop tobacco dependence during the adolescence and young adulthood. Thus, full understanding of the risk mechanisms of tobacco dependence is critical for multilevel interventions to reduce the risk of developing tobacco dependence. Although individual-level genetic and nongenetic risk factors for tobacco dependence have been established, only few prospective studies have assessed neighborhood effects on smoking behaviors. The role of neighborhood conditions and gene- neighborhood interplays in the development of tobacco dependence, particularly among adolescents and young adults, remain unclear. In addition, as a common event in longitudinal studies, mobility-induced change of neighborhood exposures may have an impact on smoking behaviors, which were ignored in the previous research and might lead to inaccurate estimations of neighborhood effects. The Missouri Adolescent Female Twin Study (MOAFTS) is a well-characterized prospective cohort study in which individual- and family-level information and residential histories were collected at baseline and updated periodically during the 20-year followup. This provides us a unique opportunity to examine the main and interactive effects of neighborhood exposures on tobacco dependence. Specifically, we will longitudinally assess the impacts of neighborhood conditions on the development of tobacco dependence (Aim 1) and characterize the geographic pattern of within-subject changes in neighborhood exposures and its effect on the development of tobacco dependence (Aim 2). Furthermore, we will prospectively examine the interactive effects of neighborhood exposures and genetic predisposition on the risk for tobacco dependence among adolescents and young adults (Aim 3). National and statewide data sources will be used to develop various small-area neighborhood measures that will be linked to the MOAFTS cohort. By integrating marginal structural modeling to multilevel behavioral genetic modeling, we will accurately assess the role of neighborhoods and gene-neighborhood interactions in tobacco dependence by controlling for mobility-induced spatial uncertainty. To our knowledge, this will be the first prospective study to comprehensively assess the role of neighborhood conditions and gene-neighborhood interplays in the development of tobacco dependence among adolescents and young adults. The results will refine our understanding of the risk mechanisms of tobacco dependence and inform multi-level strategies for reducing tobacco dependence among adolescents and young adults, ultimately reducing the burden of tobacco-related diseases.